排序方式: 共有7条查询结果,搜索用时 15 毫秒
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Wang K Diskin SJ Zhang H Attiyeh EF Winter C Hou C Schnepp RW Diamond M Bosse K Mayes PA Glessner J Kim C Frackelton E Garris M Wang Q Glaberson W Chiavacci R Nguyen L Jagannathan J Saeki N Sasaki H Grant SF Iolascon A Mosse YP Cole KA Li H Devoto M McGrady PW London WB Capasso M Rahman N Hakonarson H Maris JM 《Nature》2011,469(7329):216-220
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Helgadottir A Manolescu A Helgason A Thorleifsson G Thorsteinsdottir U Gudbjartsson DF Gretarsdottir S Magnusson KP Gudmundsson G Hicks A Jonsson T Grant SF Sainz J O'Brien SJ Sveinbjornsdottir S Valdimarsson EM Matthiasson SE Levey AI Abramson JL Reilly MP Vaccarino V Wolfe ML Gudnason V Quyyumi AA Topol EJ Rader DJ Thorgeirsson G Gulcher JR Hakonarson H Kong A Stefansson K 《Nature genetics》2006,38(1):68-74
Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group. 相似文献
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Kugathasan S Baldassano RN Bradfield JP Sleiman PM Imielinski M Guthery SL Cucchiara S Kim CE Frackelton EC Annaiah K Glessner JT Santa E Willson T Eckert AW Bonkowski E Shaner JL Smith RM Otieno FG Peterson N Abrams DJ Chiavacci RM Grundmeier R Mamula P Tomer G Piccoli DA Monos DS Annese V Denson LA Grant SF Hakonarson H 《Nature genetics》2008,40(10):1211-1215
Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively. 相似文献
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Hakonarson H Grant SF Bradfield JP Marchand L Kim CE Glessner JT Grabs R Casalunovo T Taback SP Frackelton EC Lawson ML Robinson LJ Skraban R Lu Y Chiavacci RM Stanley CA Kirsch SE Rappaport EF Orange JS Monos DS Devoto M Qu HQ Polychronakos C 《Nature》2007,448(7153):591-594
Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits. 相似文献
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The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke 总被引:29,自引:0,他引:29
Helgadottir A Manolescu A Thorleifsson G Gretarsdottir S Jonsdottir H Thorsteinsdottir U Samani NJ Gudmundsson G Grant SF Thorgeirsson G Sveinbjornsdottir S Valdimarsson EM Matthiasson SE Johannsson H Gudmundsdottir O Gurney ME Sainz J Thorhallsdottir M Andresdottir M Frigge ML Topol EJ Kong A Gudnason V Hakonarson H Gulcher JR Stefansson K 《Nature genetics》2004,36(3):233-239
We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall. 相似文献
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Mossé YP Laudenslager M Longo L Cole KA Wood A Attiyeh EF Laquaglia MJ Sennett R Lynch JE Perri P Laureys G Speleman F Kim C Hou C Hakonarson H Torkamani A Schork NJ Brodeur GM Tonini GP Rappaport E Devoto M Maris JM 《Nature》2008,455(7215):930-935
Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy. 相似文献
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Ikram MA Fornage M Smith AV Seshadri S Schmidt R Debette S Vrooman HA Sigurdsson S Ropele S Taal HR Mook-Kanamori DO Coker LH Longstreth WT Niessen WJ DeStefano AL Beiser A Zijdenbos AP Struchalin M Jack CR Rivadeneira F Uitterlinden AG Knopman DS Hartikainen AL Pennell CE Thiering E Steegers EA Hakonarson H Heinrich J Palmer LJ Jarvelin MR McCarthy MI Grant SF St Pourcain B Timpson NJ Smith GD Sovio U;Early Growth Genetics Consortium Nalls MA Au R Hofman A Gudnason H van der Lugt A Harris TB 《Nature genetics》2012,44(5):539-544
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. 相似文献
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